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Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents.

Chang J, Guo JT, Du Y, Block T - Emerg Microbes Infect (2013)

Bottom Line: Therefore, a drug that is safe and effective against both would be an enormous breakthrough.Drugs that inhibit this pathway would be expected to be selectively antiviral.In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, Drexel University College of Medicine , Doylestown, PA 18902, USA ; The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA.

ABSTRACT
Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

No MeSH data available.


Related in: MedlinePlus

Modifications of the imino sugar NBDNJ that greatly improve antiviral activity but not enzyme inhibitory activity. The imino sugar NBDNJ is a butylated DNJ with millimolar antiviral activity in vitro. Alterations of its side chain as represented in compounds CM-10-18 and IHVR-19029, improve antiviral activity by up to 1000-fold, but only modestly improve enzyme inhibition. This is presumably because the improvements are largely related to cell access. See text. ND, not done.
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fig2: Modifications of the imino sugar NBDNJ that greatly improve antiviral activity but not enzyme inhibitory activity. The imino sugar NBDNJ is a butylated DNJ with millimolar antiviral activity in vitro. Alterations of its side chain as represented in compounds CM-10-18 and IHVR-19029, improve antiviral activity by up to 1000-fold, but only modestly improve enzyme inhibition. This is presumably because the improvements are largely related to cell access. See text. ND, not done.

Mentions: However, as indicated, one major limitation for developing imino sugar antivirals has been the lack of potency and/or poor pharmacokinetic properties, which lead to difficulty in maintaining therapeutic drug concentrations in vivo. We have improved the antiviral potency of imino sugars from the platform (NBDNJ) by more than 500-fold (Figure 2). For example, based upon the encouraging in vivo efficacy results achieved with Dengue mouse models, we have synthesized imino sugar glucosidase inhibitors, represented by tert butyl urea (u) DNJ (19029), with submicromolar antiviral activity against four families of hemorrhagic fever viruses in cultured cells.37 In addition, significant in vivo efficacy in Ebola and Marburg virus infected animals has also been achieved (70%–80% protection).


Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents.

Chang J, Guo JT, Du Y, Block T - Emerg Microbes Infect (2013)

Modifications of the imino sugar NBDNJ that greatly improve antiviral activity but not enzyme inhibitory activity. The imino sugar NBDNJ is a butylated DNJ with millimolar antiviral activity in vitro. Alterations of its side chain as represented in compounds CM-10-18 and IHVR-19029, improve antiviral activity by up to 1000-fold, but only modestly improve enzyme inhibition. This is presumably because the improvements are largely related to cell access. See text. ND, not done.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924557&req=5

fig2: Modifications of the imino sugar NBDNJ that greatly improve antiviral activity but not enzyme inhibitory activity. The imino sugar NBDNJ is a butylated DNJ with millimolar antiviral activity in vitro. Alterations of its side chain as represented in compounds CM-10-18 and IHVR-19029, improve antiviral activity by up to 1000-fold, but only modestly improve enzyme inhibition. This is presumably because the improvements are largely related to cell access. See text. ND, not done.
Mentions: However, as indicated, one major limitation for developing imino sugar antivirals has been the lack of potency and/or poor pharmacokinetic properties, which lead to difficulty in maintaining therapeutic drug concentrations in vivo. We have improved the antiviral potency of imino sugars from the platform (NBDNJ) by more than 500-fold (Figure 2). For example, based upon the encouraging in vivo efficacy results achieved with Dengue mouse models, we have synthesized imino sugar glucosidase inhibitors, represented by tert butyl urea (u) DNJ (19029), with submicromolar antiviral activity against four families of hemorrhagic fever viruses in cultured cells.37 In addition, significant in vivo efficacy in Ebola and Marburg virus infected animals has also been achieved (70%–80% protection).

Bottom Line: Therefore, a drug that is safe and effective against both would be an enormous breakthrough.Drugs that inhibit this pathway would be expected to be selectively antiviral.In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, Drexel University College of Medicine , Doylestown, PA 18902, USA ; The Institute of Hepatitis and Virus Research , Doylestown, PA 18902, USA.

ABSTRACT
Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

No MeSH data available.


Related in: MedlinePlus